Pilot study on esketamine response in treatment-resistant depression: impact of pharmacogenetic, clinical, and demographic variables

Introduction: Esketamine, the S-enantiomer of ketamine, is a rapid-acting antidepressant approved for treatment-resistant depression (TRD) when used in combination with an oral antidepressant. Identifying reliable clinical or genetic predictors of treatment response remains a critical unmet need. This study aimed to evaluate the impact of selected clinical and genetic variables on esketamine response in a real-world TRD cohort. Methods: (rs1799971) polymorphisms, and CYP2B6, CYP2C9, and CYP3A4 metabolizer status. Results: No single demographic, clinical, or genetic variable reliably predicted treatment response. Adjunctive psychotherapy emerged as the only factor significantly associated with remission. Because most patients reached the standard 84 mg dose under the protocol, nominal dosing explained little of the observed variability in outcomes. Exploratory analyses suggested that metabolic phenotype and concomitant pharmacotherapy may contribute to inter-individual differences in treatment response. Discussion and Conclusions: In real-world TRD care, variability in esketamine response appears to be driven less by patient selection or nominal dose and more by a combination of pharmacologic exposure, biological factors, and psychotherapeutic engagement. These findings support a multidimensional, clinically oriented approach to treatment optimization rather than reliance on a single predictor. Given the limited sample size, the study may have been underpowered to detect modest associations, and the results should be therefore considered exploratory. Future research should prioritize the co-optimization of dosing strategies and psychotherapeutic engagement in routine care, and confirm these findings in larger, prospective studies.